Prostaglandin derivatives

ABSTRACT

Prostaglandin type compounds of the formula ##STR1## where X is CH 2  --CH 2 , CH═CH cis or C.tbd.C; Y is CH 2  or O; Z is H, OH, CH 3  or CH 2  OH and R is a linear, branched or cyclo alkyl chain of 3 to 7 carbon atoms, can be prepared by essentially a one-step reaction from a new intermediate of the formula ##STR2## where R represents a linear, branched or cyclo alkyl group of 3 to 7 carbon atoms; P is a removable protective group and z is H, OP,CH 3  or CH 2  OP. 
     The intermediate is useful in making known and new PGEs useful as antihypertensives, gastric acid secretion inhibitors and smooth muscle stimulants.

BACKGROUND OF THE INVENTION

This is a continuation-in-part of U.S. Ser. No. 746,021 filed on Nov.30, 1976, now abandoned, which is a divisional of U.S. Ser. No. 647,822filed on Jan. 9, 1976, now abandonded.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel prostaglandin intermediates, and moreparticularly novel prostaglandin E intermediates leading to new PGEshaving useful physiological properties.

2. Description of the Prior Art

The prostaglandins comprise one of the most unique and remarkable groupsof chemical compounds to emerge in recent years. Extensive research withthese agents, conducted largely during the last decade, has provided newinsights in the fundamental biological processes and has offered apromise of new potent therapeutic agents.

Chemically, prostaglandins are fatty acids of usually about 20 carbonatoms which contain a 5-membered ring, having 2 attached aliphatic sidechains, one carrying a carboxylic acid group at the terminus.

The basic structure, prostanoic acid, is shown as I. ##STR3## Chemicalvariations, involving hydroxyl, carbonyl, and structural variances suchas unsaturated groups form the various prostaglandins. An abbreviationsystem for naming these agents is widely used. Following the letters ofPG (prostaglandin), the designation of A, B, E, and F is used to denotethe specific ring structure. For example, prostaglandin E₁ (PGE₁) hasthe following structure: ##STR4## Prostaglandin E₂ (PGE₂) has thefollowing structure: ##STR5##

For a discussion of the stereochemistry of the prostaglandins, referenceis made to Nature, vol. 212, page 38 (1966).

The prostaglandins are synthesized in the body from poly-unsaturatedfatty acids by the formation of a 5-membered ring (cyclopentane ring)and incorporation of three oxygen atoms at certain positions. One of thecommon fatty acid precursors who are natural prostaglandins isarachidonic acid, the precursor of prostaglandin E₂. The main source ofarachidonic acid is the phospholipids, which are found in the cellmembrane.

The PGE₂ compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.PGE₂ is also useful as an hypotensive agent to reduce blood pressure inmammals, including man. PGE₂ also increases the flow of blood in themammalian kidney, thereby increasing volume and electrolyte content ofthe urine. Therefore, the compound is useful in managing cases of renaldisfunction, especially those involving blockage of the renal vascularbed.

DETAILED DESCRIPTION OF THE INVENTION

The new intermediates of this invention are used to produce newprostaglandins related to the PGE series which, in turn, are potentvasodilators, gastric secretion inhibitors and smooth muscle stimulantssimilar to PGE, and PGE₂. The naturally occurring prostaglandin E's aresubject to rapid metabolic change and therefore have a very shorthalf-life in the body. The novel derivatives described herein haveuseful pharmacological properties similar to PGEs, but have a muchlonger half-life in the body because of their increased resistance tometabolic change.

The compounds of the present invention have the formula ##STR6## whereinZ is H, OH, CH₃, CH₂ OH, R is a linear, branched or cyclo alkyl chain of3 to 7 carbons, and P is hydrogen or a protective group that can beremoved without affecting the rest of the molecule.

It has been found that the new analogs of PGEs of various α-chains canbe made through a new synthetic route (FIG. 1) involving, as a newintermediate, the above 5-membered ring of formula IV. This intermediatecan then be treated, in known fashion, to prepare PGs resembling thoseof known configuration. These new end products are prepared byessentially a one-step reaction with the current, novel intermediate offormula IV where R represents a linear, branched or cyclo alkyl group of3 to 7 carbon atoms; P is a removable protective group; and Z is H, OP,CH₃ or CH₂ OP.

The novel preparation of the modified PGs involves the 1, 4-addition ofa cuprate reagent (containing the entire ω-chain) to the compound of theformula ##STR7## producing IV. The latter is converted to modified PGEanalogs through a second alkylation, α to the carbonyl, in which theentire α-chain is added.

The end products of the formula ##STR8## which are made from the currentintermediates, possess interesting pharmacological properties whentested in standard pharmacological tests. In particular, they have beenfound to possess hypotensive, antihypertensive and gastric acidsecretion inhibiting properties which make them useful in the treatmentof conditions associated with high blood pressure and in the treatmentof pathological conditions associated with excessive secretion ofgastric acid such as, for example, peptic ulcer.

When the compounds of this invention are employed as hypotensive oranti-hypertensive agents, as agents inhibiting gastric acid secretion inwarm-blooded animals, for example, in cats or rats, as agents for theprevention or treatment of thrombosis, or as bronchospasmolytic agents,alone or in combination with pharmaceutically acceptable carriers, theirproportions are determined by their solubilities, by the chosen route ofadministration, and by standard medicinal practice. The compounds ofthis invention may be administered orally in solid form containing suchexcipients as starch, lactose, sucrose, certain types of clay, andflavoring and coating agents. However, they are preferably administeredparenterally in the form of sterile solutions thereof which may alsocontain other solutes, for example, sufficient sodium chloride orglucose to make the solution isotonic. For use as broncho-spasmolyticagents, the compounds of this invention are preferably administered asaerosols.

The dosage of the present hypotensive, anti-hypertensive, gastric acidsecretion inhibiting, or broncho-spasmolytic agents, or agents for theprevention and treatment of thrombosis will vary with the forms ofadministration and the particular hosts under treatment. Generally,treatments are initiated with small dosages substantially less than theoptimum doses of the compounds. Thereafter, the dosages are increased bysmall increments until the optimum effects under the circumstances arereached. In general, the compounds of this invention are most desirablyadministered at a concentration level that will generally affordeffective results without causing any harmful or deleterious sideeffects and preferably at a level that is in a range of from about -10μg/kg, although as aforementioned variations will occur. However, adosage level that is in range of from about 0.5 mg to about 5 mg perkilo is most desirably employed in order to achieve effective results.When administering the compounds of this invention as aerosols theliquid to be nebulized, for example, water, ethyl alcohol,dichlorotetrafluoroethane and dichlorodifluoromethane, containspreferably from 0.005-0.05 percent of the acid, or a non-toxic alkalimetal, ammonium or amine salt thereof, or ester of formula IV.

Practical and presently preferred embodiments of the present inventionwill be illustrated in the following examples, and reference should bemade to FIGS. 1 and 2. However, these examples are not intended to limitthe invention in any respect other than as defined in the Claims.

EXAMPLE 1 Preparation of3-(3'-t-butyldimethylsilyloxy-1'-octenyl)-γ-valerolactone (IV: R═nC₅ H₁₁; Z═CH₃)

t-BuLi (20 ml; 0.75 M) was rapidly added to1-iodo-3-t-butyldimethyl-silyloxy-trans-1-octene) (obtained as describedby Corey JACS 94, 7210 (1972)) (2.85 g; 7.5 mmoles) at -78° under argon.The mixture was stirred at that temperature for two hours.Independently, nBu₃ P (1 ml) was added to a suspension of CuI (715 mg;3.75 mmoles) in 20 ml of ether. After ten minutes, this clear solutionwas slowly added to the solution of the above octene. The resultingmixture was stirred for one hour. At that point the solution was afaintly yellow suspension.

β-Angelicalactone (367 mg; 3.75 mmoles) was added dropwise. The solutionturned dark brown instantly. Stirring was continued at -78° for thirtyminutes, then the flask was placed on a CCI₄ /dry ice bath and theinternal temperature rose slowly to -35°. When the temperature rose from-35° to -15°, the solution gradually lost its color. The mixture wasstirred at -15° for thirty minutes and HCl (1 N) was added (at -15°).Extraction, washing with NH₄ Cl solution, and concentration of theether, afforded a mobile colorless syrup.

The product was separated from the less polar residue by chromatographyon silicia gel eluted with petroleum ether (30°-60°). The residue ofcompound 2 (1.53 g) was pure enough for the subsequent steps.

An aliquot was purified by preparative thin-layer chromatography,hereinafter called tlc (petroleum ether: ether; 4:1); IR 1790 cm⁻¹ γlactone, NMR; 5:55 (2 H; m; H₁₃ ; H₁₄) 4.30-3.90 (2 H; m; H₁₁ ; H₁₅).

By replacing the named starting material by the corresponding hexene,heptene, undecene, cyclohexylbutene, cyclobutylpentene, 5-methyloctene,6-methylheptene (R═nC₃ H₇ --; nC₄ H₉ --; nC₈ H₁₇ -- ##STR9## CH₃ CH₂ CH₂CH(CH₃)--CH₂ --; (CH₃)₂ CH(CH₂)₂ --) etc., other analogs of IV areobtained in the described fashion.

EXAMPLE 2 Preparation of methyl 7-iodo-cis-5-heptenoate

Methyl 7-hydroxy-5-heptynoate (3.9 g) was hydrogenated in the presenceof Pd/C 5% (400 mg) and quinoline (1 g) in methanol (50 ml). The mixturewas filtered and the methanol concentrated; then the residue wasdissolved in dichloromethane and washed twice with water, dried andconcentrated to give 3.8 g. The product (3.8 g; 24 mmoles) was stirredat room temperature for six hours with (PhO)₃ PCH₃ I (12.4 g; 27 mmoles)in CH₂ Cl₂ /DMF (20 ml, 5 ml). After the organic phase was washed withwater, dried and concentrated, the residue was purified on columnchromatography and eluted with petroluem ether (30°-60°).

EXAMPLE 3 Preparation of 11-deoxy-11-methyl-10-oxa-prostaglandin E₂methyl ester (3; Z═CH₃)

nBuLi (2.16 ml; 4.32 mmoles) was rapidly added to diisopropylamine (0.65ml; 4.32 mmoles) in THF (12 ml) at 0°. The mixture was stirred at 0° forone hour, then cooled at -78°. A solution of 2 (1.471 g; 4.32 mmoles) in2 ml THF was added dropwise. After stirring at -78° for one hour, theiodide of Example 2 (1.16 g; 4.32 mmoles) was added. The mixture wasplaced on a CCl₄ /dry ice bath. Color changes occurred as thetemperature rose above -60°. After stirring one more hour at -30° to-15°, HCl (1 N) was added (at -15°). The product was extracted withether, washed and concentrated to give 1.982 g of colorless residue.

An aliquot (339 mg) was purified by preparative tlc to afford the puresilyl ether (84 mg; 28% overall yield) derivative 3a.

The remaining crude silyl derivative (1.643 g) was treated with Bu₄ NF(10 ml; 10 mmoles) to afford crude 3 (1.507 g) which was purified bypreparative tlc (13 plates) eluted with petroleum ether: ether; (4:1).The product showed two close spots, diastereomers at positions 11 and15. Overall yield from angelicalactone: 396 mg (29%).

EXAMPLE 4

The methyl ester of Example 3 was hydrolyzed to the free acid, CompoundVI (X=CH═CH cis, Y=CH₂, Z=CH₃, R=n--C₅ H₁₁) using sodium hydroxide (2eq) in water: THF (1:1).

By using the compounds identified in the last paragraph of Example 1 andproceeding according to Examples 2-4, the corresponding 10-oxa-analogsof PGEs of formula VI are obtained, carrying the R groups named inExample 1 last paragraph.

EXAMPLE 5 Preparation of5,6-dehydro-11-deoxy-11-methyl-10-oxa-prostaglandin E₂

Replacing the iodide of Example 2 by methyl 7-iodo-5-heptynoate(obtained as described in Corey JACS, 95, 8483 (1973) in the procedureof Example 3, followed by saponification of the methyl ester, yieldedcompound VI (X═C.tbd.C, Y═CH₂, Z═CH₃, R═n--C₅ H₁₁) as a colorless syrupsimilar in physical properties to the product of Example 4. ##STR10##where P is a protective group such as t-butyldimethylsilyltetrahydropyranyl, or equivalents thereof selected from the protectivegroups described by MCOMIE, Advances in Organic Chemistry, Methods andResults, Vol. 3, page 216-51 and the Table of page 273 (1963). ##STR11##

EXAMPLE 6 Preparation of methyl-O-(4-hydroxy-2-butynyl)-glycolate (5)

To 2-butyn-1,4-diol (300 g; 3.49 moles) in dioxane (800 ml) in thepresence of p-TSOH (3 g), was added dihydropyran (294 g; 3.5 moles)during a period of six hours. The medium was stirred overnight at roomtemperature then neutralized with solid K₂ CO₃. The solvent was removedwithout filtration and the residue was dissolved in dichloromethane andwashed twice with water. The organic phase was dried, concentrated anddistilled to afford the mono tetrahydropyranyl derivative (205 g; 34%)b.p. 92°-98°/0.2 mmHg. This derivative (110 g; 0.649 mole) was added allat once to a solution of potassium t-butoxide freshly prepared frompotassium (25.3 g; 0.649 mole) in t-BuOH (600 ml). After three minutes,methyl bromoacetate was added (97.35 g; 0.649 mole). The temperaturerose spontaneously to 70°. When the exothermic reaction was completed,the mixture was found to be neutral and the solvent was evaporated undervacuum. The residue (140 g; 88%) was found to be homogeneous on tlc (andwas not purified at that stage), and was then heated under reflux inmethanol (700 ml) containing a small amount of p-TSOH. After thirtyminutes, the medium was allowed to cool down and 0.1 ml of pyridine wasadded; the solvent was evaporated and the residue distilled, giving theintermediate 4 (FIG. 2) (81.4 g; 89%) b.p. 110°-120°/3 mmHg.

It was hydrogenated as in Example 2 to afford an almost quantitativeyield of the cis-alkene, which was iodinated as in Example 2 to afford 5in 85% yield after chromatography. Compound 5 was found to be unstableand was stored cold under argon. (FIG. 2).

EXAMPLE 7 Preparation of 11-deoxy-3,10-dioxa-11-methyl-prostaglandin E₂

The title compound of formula VI wherein X=--CH═CH-- cis; Y=O; Z=CH₃ ;and R=n--C₅ --H₁₁ was prepared by using the iodide 5 (FIG. 2) in theprocedures of Examples 3 and 4.

EXAMPLE 8 Preparation of methyl 0-[1-(4-iode-2-butynyl)]-glycolate

Iodination of 4 (FIG. 2) by the procedure described in Example 2 gavethe desired iodoalkyne 5 (FIG. 2).

EXAMPLE 9 Preparation of 5,6-dehydro-11-deoxy-3,10-dioxa-11-methylprostaglandin E₂

The title compound of formula VI wherein X=C.tbd.C; Y=O; Z=CH₃ ; andR=(CH₂)₃ CH₃ was prepared by using the iodide 6 (FIG. 2) in theprocedures of Examples 3 and 4.

EXAMPLE 10

The preparation of the analogs of the parent11-deoxy-10-oxa-11-substituted PGEs, having a different number of carbonatoms on the ω-chain, was performed as in Examples 1, 3 and 4 exceptthat the appropriate 1-iodo-4-alkenes were used (total chain lengths 6,7, 9 and 10).

EXAMPLE 11 Preparation of3-t-butyldimethylsilyloxy-4-(3'-t-butyldimethylsilyloxy-1'-octenyl)-.gamma.-valerolactone

Replacement of β-angelicalactone with 5-hydroxy-2-penten-4-olide[obtained as described by Front [Soc. Espan. Fis. Quim. 62. 477 (1966)]in the procedure of Example 1 and protecting its hydroxy group witht-butylidmethylsilyl yielded intermediate 2 (Z=CH₂ OP).

Replacement of 2 (FIG. 1) by the above lactone in the procedures ofExamples 3 and 4 yielded modified prostaglandins VI wherein Z=CH₂ OH,the other variations being unaffected.

While the above examples are directed to the use of thet-butyldimethylsilyl group for protection of the otherwise reactivehydroxy groups, almost identical results are obtained by using the morecommonly used protective ability of the tetrahydropyranyl group. Anynumber of other protective groups can be used, as is well recognized bythose skilled in the art, each group having its own characteristics andreactivity for insertion in the molecule or the removal from the finalPG analog made by use of the current intermediates.

What is claimed is:
 1. A compound of the formula ##STR12## wherein R isa linear, branched or cyclic alkyl group of 3-7 carbons, P is aprotective group that can be removed chemically without affecting therest of the molecule, and Z is OP, CH₃ or CH₂ OP.
 2. A compoundaccording to claim 1 wherein R is a pentyl group and Z is methyl.
 3. Thecompound of claim 2 wherein R is n-pentyl and P is t-butyldimethylsilyl.4. The compound of claim 2 wherein R is n-pentyl and P istetrahydropyranyl.
 5. A compound according to claim 1 wherein Z is CH₂OP or CH₃, R is n-pentyl.
 6. The compound of claim 5 wherein P ist-butyldimethylsilyl.
 7. The compound of claim 5 wherein P istetrahydropyranyl.